Nutrient‐sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis

Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of > 3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a novel mechanism. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia‐reperfusion injury in murine models. Nutrient‐sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.